HDAC inhibitors still need a home run, despite recent approval

Guha, Malini

doi:10.1038/nrd4583

Cited by 120Histone Deacetylase Inhibitors ResearchEpigenetics and DNA MethylationProtein Degradation and Inhibitors

HDAC inhibitors still need a home run, despite recent approval

Guha, Malini·2015·Nature Reviews Drug Discovery

DOI 10.1038/nrd4583

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Dose-limiting adverse effects such as cardiac toxicity associated with hERG K+ channel activation hinder progress of HDAC inhibitors in the clinic.
“Importantly, dose-limiting adverse effects such as cardiac toxicity associated with hERG K+ channel activation are hindering their progress in the clinic [133, 134].”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [133]

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“However, due to the pan-HDACi toxicity, class- or isoform-selective HDACi should be preferred in a clinical setting to reduce side effects, especially when used in combination with other treatments (Guha 2015).”
Background
HDAC1 and HDAC2 regulate anti‐inflammatory effects of anesthetic isoflurane in human monocytes
Guo, X., Deng, J., Zheng, B., Liu, H., Zhang, Y., Ying, Y., Jia, J., & Ruan, X. (2020) · Immunology and Cell Biology · doi:10.1111/imcb.12318 · Cited by 18 · see citing works
“HDAC inhibitors have gained significant attention as potential epigenetic cancer treatments, and several HDAC inhibitors have been approved for anticancer therapy.(17) Thus, concomitant administration of HDAC inhibitors would abolish the beneficial anti-inflammatory effects of volatile anesthetics in these patients.”
Background
Characterization of Renal Cell Carcinoma Heterotypic 3D Co-Cultures with Immune Cell Subsets
Rausch, M., Blanc, L., Silva, O. D. S., Dormond, O., Griffioen, A. W., & Nowak-Sliwinska, P. M. (2021) · Cancers · doi:10.3390/cancers13112551 · Cited by 18 · see citing works
“In ccRCC, HDAC are attractive targets, but the use of single HDACI has failed clinical investigation so far [78,79].”
Background
Molecular Mechanisms of Epigenetic Regulators as Activatable Targets in Cancer Theranostics
Li, Y., Li, Z., & Zhu, W. (2019) · Current Medicinal Chemistry · doi:10.2174/0929867324666170921101947 · Cited by 19 · see citing works
Histone Deacetylase Inhibitors: A Prospect in Drug Discovery
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Novel 4-Oxoquinazoline-BasedN-Hydroxypropenamides as Histone Deacetylase Inhibitors: Design, Synthesis, and Biological Evaluation
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Mullard, A. (2015) · Nature Reviews Drug Discovery · doi:10.1038/nrd4582 · Cited by 17 · see citing works
Discovery of a novel HDACi structure that inhibits the proliferation of ovarian cancer cells in vivo and in vitro
Bai, M., Cui, M., Li, M., Yao, X., Wu, Y., Zheng, L., Sun, L., Song, Q., Wang, S., Liu, L., et al. (2021) · International Journal of Biological Sciences · doi:10.7150/ijbs.62339 · Cited by 18 · see citing works
“The anticancer mechanisms of HDACis also need further research [26].”
Background
HDAC5 Inhibits Hepatic Lipogenic Genes Expression by Attenuating the Transcriptional Activity of Liver X Receptor
Jia, H.-Y., Li, Q., & Lv, L.-F. (2016) · Cellular Physiology and Biochemistry · doi:10.1159/000447858 · Cited by 18 · see citing works
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“HDAC inhibitors have already been approved by the Food and Drug Administration (FDA) for the treatment of T-cell malignancies (73 – 75).”
Background
Design, synthesis and biological evaluation of novel histone deacetylase inhibitors incorporating 4-aminoquinazolinyl systems as capping groups
Zhang, Q., Li, Y., Zhang, B., Lu, B., & Li, J. (2017) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2017.09.036 · Cited by 16 · see citing works
Molecular design, synthesis and in vitro biological evaluation of thienopyrimidine–hydroxamic acids as chimeric kinase HDAC inhibitors: a challenging approach to combat cancer
Abdel-Atty, M. M., Farag, N. A., Serya, R. A. T., Abouzid, K. A. M., & Mowafy, S. (2021) · Journal of Enzyme Inhibition and Medicinal Chemistry · doi:10.1080/14756366.2021.1933465 · Cited by 17 · see citing works
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“HDAC inhibitors (HDACIs) have been identified as anticancer agents (Drummond et al., 2005; Guha, 2015; Mottamal, Zheng, Huang, & Wang, 2015; Qiao et al., 2013), immune modulators (Adcock, Ito, & Barnes, 2005; Choi & Reddy, 2011; Dinarello, Fossati, & Mascagni, 2011; Faraco, Cavone, & Chiarugi,…”
The Roles of Histone Deacetylases in the Regulation of Ovarian Cancer Metastasis
Xu, L., Yan, X., Wang, J., Zhao, Y., Liu, Q., Fu, J., Shi, X., & Su, J. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms242015066 · Cited by 16 · see citing works
“In general, HDACIs are unable to speciﬁcally target certain isoforms in the subclass of HDACs [150].”
Background
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Dung, D. T. M., Pham‐The, H., Anh, D. T., Le‐Thi‐Thu, H., Yen, N. T. K., Han, B. W., Park, E. J., Choi, Y. J., Kang, J. S., Huệ, V. T. M., et al. (2018) · Journal of Chemical Sciences · doi:10.1007/s12039-018-1472-x · Cited by 14 · see citing works
Synthesis and Anticancer Research of N ‐(2‐aminophenyl)benzamide Acridine Derivatives as Dual Topoisomerase I and Isoform‐Selective HDAC Inhibitors
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A novel benzamine lead compound of histone deacetylase inhibitor ZINC24469384 can suppresses HepG2 cells proliferation by upregulating NR1H4
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Antiandrogen-Equipped Histone Deacetylase Inhibitors Selectively Inhibit Androgen Receptor (AR) and AR-Splice Variant (AR-SV) in Castration-Resistant Prostate Cancer (CRPC)
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CXCL1 Clone Evolution Induced by the HDAC Inhibitor Belinostat Might Be a Favorable Prognostic Indicator in Triple‐Negative Breast Cancer
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“It has been reported that limited penetration and extensive tissue distribution result in clinical ineffectiveness and off-target effects, such as myelosuppression, fatigue, and cardiac toxicity [9].”
Background
Quantitative Acetylomics Uncover Acetylation-Mediated Pathway Changes Following Histone Deacetylase Inhibition in Anaplastic Large Cell Lymphoma
Zrimšek, M., Kuchaříková, H., Draganić, K., Dobrovolná, P., Spornberger, V. H., Winkelmayer, L., Hassler, M. R., Lochmanová, G., Zdráhal, Z., & Egger, G. (2022) · Cells · doi:10.3390/cells11152380 · Cited by 9 · see citing works
Exploring Derivatives of Quinolizidine Alkaloid Sophoridine in the Design and Biological Mechanistic Evaluation of Histone Deacetylase Inhibitors against Triple‐Negative Breast Cancer
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Erratum: HDAC inhibitors still need a home run, despite recent approval
Guha, M. (2015) · Nature Reviews Drug Discovery · doi:10.1038/nrd4632 · Cited by 8 · see citing works
Self-citation
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Class I and II Histone Deacetylase Inhibitor LBH589 Promotes Endocrine Differentiation in Bone Marrow Derived Human Mesenchymal Stem Cells and Suppresses Uncontrolled Proliferation
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Effect of phenylurea hydroxamic acids on histone deacetylase and VEGFR-2
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Authors: Guha, M.
Corresponding author: Guha, Malini
Venue: Nature Reviews Drug Discovery
Publisher: Springer Science and Business Media LLC
Published: 2015-04
Volume: 14
Issue: 4
Pages: 225-226
ISSN: 1474-1776 (ISSN-L)
1474-1784
DOI: 10.1038/nrd4583
OpenAlex: W2033780602
Cited by: 120
References: 0
Citations by year: 2026: 5 · 2025: 3 · 2024: 8 · 2023: 9 · 2022: 8 · 2021: 14 · 2020: 18 · 2019: 11 · 2018: 9 · 2017: 16 · 2016: 12 · 2015: 7
Type: other
Language: en
Update notices: erratum (2015-04-30)
Open access: closed
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Nature Reviews Drug Discovery (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
Keywords: histone deacetylase inhibitors, epigenetic regulators, cancer therapy, drug approval
MeSH terms: Histone Deacetylases, Humans, Multiple Myeloma, United States, United States Food and Drug Administration, Drug Approval, Epigenesis, Genetic, Histone Deacetylase Inhibitors

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